Combined Hydrogel/Microparticle Eye Drops for Sustained Delivery of Glaucoma Medication Glaucoma is the second leading cause of blindness worldwide and costs $2.5B to treat every year in the US alone. Topical eye drops are the current clinical standard in treating glaucoma and numerous other ocular pathologies. However, the frequent and difficult administration of eye drops makes them highly inefficient, with patient compliance in some cases as low as 50%. Poor compliance puts patients at risk for worsening vision and blindness, with a significant increase in treatment costs. Both patients and clinicians would benefit greatly from a more efficient treatment method that would increase patient compliance and deliver drug more efficiently to the aqueous humor to avoid systemic toxicity. Contact lenses and novel eye drops including nanoparticles are a comfortable and familiar alternative to traditional eye drops, but have only extended delivery windows to several hours or days at most. In contrast, formulations that can provide weeks to months of drug release currently require injection or implantation into the eye by a clinician. If an ocular deliery strategy could combine the comfort and simplicity of an eye drop with long-term drug delivery, it could revolutionize the delivery of not only glaucoma medication, but other ocular medications as well. The goal of this project is to develop a new, easy-to-administer, and noninvasive treatment capable of long- term release of glaucoma medication to the eye. Such a formulation would dramatically reduce patient compliance-related complications due to the simple, patient-administered format and the marked decrease in dosing frequency. The consequences of systemic toxicity and insufficient ocular absorption inherent to eye drops would be mitigated with a more direct delivery of over 100x less drug. Using a combined approach of highly customizable, polymer microparticle (MP)-controlled delivery of brimonidine tartrate (BT) contained in an in situ forming gel eye drop will provide a comfortable and vastly more efficient delivery format for the treatment of glaucoma. The gel eye drop is intended for administration to the lower fornix, where it comfortably conforms to the conjunctival cul-de-sac and releases drug for up to 30 days. The project's primary objective is to optimize custom-designed MPs to release therapeutic levels of BT and engineer a thermoresponsive, hydrogel matrix for retaining the MPs. In silico modeling methods will be used to develop the drug delivery system, followed by requisite in vitro validation of drug release kinetics. The gel/MP system will be tested in a rabbit model of ocular hypertension to demonstrate clinically relevant results and sustained BT delivery. Finally, this new drug delivery system will be evaluated as a platform for treating othe ocular diseases by using noninvasive magnetic resonance imaging (MRI) to monitor drug release and distribution in vivo. Ultimately, this work represents the initiation of preclinical efficacy and safety testing of a modular strategy for delivering of a variety of ocular therapeutic using novel in vivo drug delivery and visualization techniques.